The main objective of our research is to understand the cellular mechanisms and interactions involved in in vivo mediated tissue destruction as exemplified by allograft and xenograft rejection. An additional project, considerably removed from the field of transplantation, has examined the anti-viral activity of restriction endonucleases. Over the past year, our studies have focused on the role of CD4(+) T cells in rejection of MHC class I disparate skin grafts and on the cellular mechanisms underlying the mouse anti-human xenograft response. We have found that, in the absence of additional alloantigenic disparities, CD4(+) T cells slow the rejection rate of MHC class I disparate skin grafts, mediated by CD8(+) T cells. We are currently exploring whether CD4(+) T cells exposed to class I alloantigen in the absence of additional cellular populations are capable of mediating complete suppression of the rejection response. In xenografting experiments, we are investigating the cellular requirements for generation of mouse CTL to human tumor cells in an effort to generate tumor specific CTL which do not depend on multiple accessory molecules. We are further characterizing the murine cellular responses to human hematopoietic progenitor cells, and thymic epithelium with the goal of establishing stable mouse-human chimeras. We have found that murine CTL responses to human alloantigens expressed on tumor cells require in vivo priming and that both CD4(+) Th cells and CD8(+) Tk cells are required. Preliminary studies have further revealed that primed effector cells may not require mouse antigen presenting cells for their activation. We are further investigating the dependency of such CTL on various accessory molecules, both human and mouse. Lastly, studies using restriction endonucleases as anti-viral agents, have revealed that restriction endonucleases with sites on dS DNA viruses (or RNA viruses whose replicative cycle involves a dsDNA form) appear to specifically inhibit infection in infected mammalian cells.